PROJECT SUMMARY Influenza virus is a serious pathogen in immunocompromised persons, especially hematopoietic stem cell transplant (HSCT) recipients. However, these individuals respond poorly to trivalent inactivated influenza vaccine (TIV). High dose (HD)-TIV has increased immunogenicity and efficacy in adults >65 years of age. It is not known whether a HD-TIV will be safe and immunogenic in severely immunocompromised persons. The standard measure of immunogenicity for TIV is hemagglutination inhibition (HAI) titers. The central hypothesis of our proposal is that HD-TIV will be more immunogenic compared to standard dose quadrivalent inactivated influenza vaccine (QIV) in adult HSCT recipients as evident by higher HAI antibody responses to influenza A antigens. The proposed study is a multi-center, phase II immunogenicity and safety trial comparing two doses of HD-TIV to standard dose QIV in adult HSCT recipients. A total of 138 patients (?18 years of age) who received an allogeneic HSCT and are 3-23 months post-transplant will be enrolled at the following clinical sites: Vanderbilt University Medical Center (lead site); Northwestern University Feinberg School of Medicine, Fred Hutchinson Cancer Research Center; University of Alabama at Birmingham School of Medicine. The specific aims are as follow: Specific Aim 1) to determine whether HD-TIV compared with standard dose QIV will increase the probability of achieving either a ?4-fold rise in HAI titer, a HAI titer ?1:40, or a higher geometric mean titer (GMT) to influenza A antigens in adult HSCT recipients; Specific Aim 2) to determine the frequency and severity of solicited local injection site adverse events and solicited systemic adverse events associated with HD-TIV compared with standard dose QIV in adult HSCT recipients; Specific Aim 3) to define the relationship between HAI titers, in vivo T and B cell phenotype, and in vitro influenza-specific T and B cell responses in adult HSCT recipients receiving either HD-TIV or standard dose QIV. Subjects will be randomized in a 1:1 fashion to receive either 2 doses of 2017-2018 HD-TIV (60g of each influenza antigen) or 2 doses of standard dose QIV (15g of each influenza antigen). HAI and microneutralization titers to influenza virus antigens, phenotypic B and T cell responses, B and T cell specific influenza responses, complete blood count, quantitative CD4+/CD8+/CD19+ levels, and quantitative serum IgG and IgM concentrations will be measured prior to the first and second vaccine dose, 28-42 days after the second vaccine dose, and approximately 7 months after second vaccine. Solicited adverse events will be recorded by the subject seven days following vaccination and a telephone/email follow-up by study staff. The results of this study will fill a gap in knowledge regarding influenza vaccine responses in HSCT recipients and will guide vaccine recommendations in this vulnerable population.